Resistant Organisms in the ICU

1
Resistant Organisms in the ICU

• Timothy H. Dellit, MD
• Assistant Professor
• Division of Allergy Infectious Diseases
• University of Washington School of Medicine
• Harborview Medical Center

2
Antimicrobial Use
Adverse Events
Pharmacy Cost
Increased Morbidity/Mortality Cost of Care
Antimicrobial Resistance
3
Emergence of Antimicrobial Resistance
Susceptible Bacteria
4
Selection for Antimicrobial-Resistant Strains
5

Increasing Incidence of Resistant Gram-Positive
Pathogens
United States, 1980-1995
100
90
80
MRSE
70
60
MRSA
()PathogensResistant toAntibiotics
50
NPSSP
40
30
20
VRE
10
GISA
0
2000
1975
1985
1990
1995
1980
1997
MMWR, July 11, 1997 46(7)624-636. Thornsberry
C. et al. 38th ICAAC, 1998, Abstract E22
6
Proportion of S. aureus Nosocomial Infections
Resistant to Oxacillin (MRSA) Among Intensive
Care Unit Patients, 1989-2003
Source NNIS System, data for 2003 are incomplete
7
Nosocomial Antimicrobial Resistance
Methicillin (oxacillin)-resistant Staphylococcus
aureus
Vancomycin-resistant enterococci
Non-Intensive Care Unit Patients Intensive Care
Unit Patients
Source National Nosocomial Infections
Surveillance (NNIS) System
8
Community-Associated MRSA

• Four pediatric deaths 1997-1999 in Minnesota and
  North Dakota (MMWR 199948707)
• Clinical manifestations
• Predominantly skin and soft tissue (JAMA
  20032902976-2984)
• Necrotizing pneumonia (Clin Infect Dis
  200540100-7)
• Necrotizing fasciitis (N Engl J Med
  20053521445-53)
• Healthcare-associated surgery, dialysis,
  indwelling devices, long-term care facilities
• Community IDU, incarceration, MSM, Athletic
  participation, and NO CLEAR RISK FACTOR
  (Clin Infect Dis 200234425-33,
  Clin Infect Dis 2003271384-8, N Engl J Med
  2005352468-75)

9
Nosocomial Antimicrobial Resistance
3rd generation cephalosporin- resistant
Klebsiella pneumoniae
Fluoroquinolone-resistant Pseudomonas aeruginosa
Non-Intensive Care Unit Patients Intensive Care
Unit Patients
Source National Nosocomial Infections
Surveillance (NNIS) System
10
Tip of the Iceberg?
760 Cases of VRE identified between Jan 1997
Oct 1999
86 undetected by clinical specimen alone
Percent of Cases Identified
Clin Infect Dis 200337326-32
11
Clinical Consequences of Antimicrobial Resistance

• Increased patient morbidity and mortality
• MRSA bacteremia associated with increased
  mortality compared to MSSA (OR 1.93) (Clin Infect
  Dis 20033653-9)
• MRSA surgical site infection associated with
  greater 90-day mortality (OR 3.4) and prolonged
  LOS (Clin Infect Dis 200336592-8)
• Increased cost of health care
• Attributable cost per case of MRSA 9,275-13,901
  (JAMA 19992821745-1751)
• Multidrug-resistant Acinetobacter baumannii
  associated with attributable cost of 98,575 in a
  burn unit (Am J Infect Control 200432342-4)

12
Acinetobacter baumanii and Carbapenems

• 2003
• Imipenem 99
• Amikacin 64
• Minocycline 20
• Cefepime 34
• Ceftazidime 19
• Pip/tazo 15
• Ciprofloxacin 15

13
HMC VAP Pathogens 7/03 6/04
394 Quantitative Bronchoscopies

• Pathogen Early Late Total
• N39 () N137 () N176 ()
• Acinetobacter 3 (8) 43 (31) 46 (26)
• MRSA 7 (18) 31 (23) 38 (22)
• Haemophilus 10 (26) 20 (15) 30 (17)
• MSSA 8 (21) 21 (15) 29 (17)
• Pseudomonas 1 (3) 13 (10) 14 (8)
• S. pneumoniae 8 (21) 1 (1) 9 (5)

Based on quantitative culture BAL gt 10,000
CFU/ml or PBS gt 1000 CFU/ml Early lt 4 days of
MV, Late gt 4 days of MV
14
VAP Pathogens in Relation to Duration of
Mechanical Ventilation
Number of VAP Cases
Days of Mechanical Ventilation
15
Current Practices 7/03- 6/04
Unnecessary inclusion of anti-pseudomonal or
Acinetobacter coverage in 33/68 (49) of patients
with suspicion of early VAP
Percent of Suspected VAP Cases
Excluded patients without empiric antimicrobial
selection and those who are on concurrent
antimicrobials for other ongoing infections or
surgical prophylaxis at the time
16
Antimicrobial Therapy in Relation to Quantitative
Bronchoscopy ResultsJuly 2003 June 2004
Positive Quantitative Culture Empiric therapy
covered pathogen 148/176
(84) De-escalation of antimicrobial therapy
108/176 (61) Inappropriately broad
definitive therapy 26/176
(15) Negative Quantitative Culture No
antimicrobials started 47/218
(22) Antimicrobials discontinued within 3 days
72/218 (33) Treatment continued for
presumed VAP 40/218 (18) Treatment
continued for non-VAP infection 59/218
(27)
17
Development of VAP Guidelines

• Consideration of bronchoscopy
• Initiation of empiric therapy
• Empiric therapy regimens
• A. Early onset VAP
• B. Late onset VAP
• De-escalation of therapy
• Duration of therapy

18
Inadequate Antimicrobial Therapy and Mortality
17
Infection-Related Mortality RR 2.37
Number of Patients
42
Chest 1999115462-74
19
Invasive Diagnosis of VAP

• Invasive Non-invasive
• Diagnosis Diagnosis
• Antimicrobial-free 11.0 7.5 p lt .001
• days (at day 28)
• Mortality (day 14) 16.2 25.8 p .022

413 patients 31 intensive care units
Ann Intern Med 2000132621-30
20
Clinical Pulmonary Infection Score
CPIS lt 6
Randomize
Ciprofloxacin for 3 days
Standard Care 10-21 days of therapy
CPIS gt 6
CPIS lt 6
At Day 3
Treat as pneumonia
Discontinue ciprofloxacin
Am J Respir Crit Care Med 2000162505-511
21
Short-Course Empiric Antimicrobial Therapy for
Low Risk Patients

• Standard Experimental
• Variable Therapy (n42) Therapy (n 39)
• Regimen clinician discretion ciprofloxacin 400mg
• (all treated 18 drugs) (IV q8h x 3 days)
• Treatment gt 3 days 97 28
• Antimicrobial duration 9.8 days 3 days
• Length of ICU stay
• mean/median 14.7 / 9 days 9.4 / 4 days
• Mortality (30 day) 31 13
• Antimicrobial resistance 35 15
• Antimicrobial cost
• mean / total 640 / 16,004 259 / 6,484

22
Duration of Therapy for VAP

• Variable 8 Days (n197) 15 Days (n204)
• Mortality 18.8 17.2
• Recurrent infection 28.9 26
• Antibiotic free days 13.1 days 8.7 days
• Antimicrobial resistance 42.1 62.0
• Recurrence rate among
• Non-lactose fermenters 40.6 25.4

JAMA 20032902588-2598
23
MRSA Nosocomial Pneumonia
p 0.03
Survival Rate
Chest 20031241789-1797
24
Empiric to Specific Therapy in VAP
Early VAP
Late VAP
Imipenem or mero vancomycin /- aminoglycoside
or ciprofloxacin
Amp/sulb, ceftriaxone, ertapenem, or moxifloxacin
(PCN all)
If GPC in clusters on gram stain, history of
MRSA, or RF for MRSA, add vancomycin
De-escalation based on quantitative culture
Consider linezolid for documented MRSA pneumonia
Standard duration of therapy 8 days except for
Pseudomonas
25
New Problem

• 32 y o man S/P MVA with multiple fractures is
  intubated and admitted to the ICU. Six days
  later he develops fever, purulent ET secretions,
  and RLL infiltrate on CXR. BAL reveals 50,000
  CFU Acinetobacter resistant to all standard
  antibiotics. What are your options?

26
Acinetobacter Perspective

• New York Hospital Queens reported nosocomial SICU
  outbreak of Acinetobacter only susceptible to
  polymyxin and sulbactam in 1991
  (Lancet 19943441329-32)
• 1997 survey of 15 hospitals in Brooklyn found
  that Acinetobacter accounted for 10 of
  gram-negative isolates, 50 were imipenem
  resistant (Clin Infect Dis 200031101-6)
• 102 patients with Acinetobacter bacteremia at
  military medical facilities (Landstuhl and Walter
  Reed) between 1/02 8/04 (MMWR
  2004531063-1066)
• Service members injured in Afghanistan and the
  Iraq/Kuwait region

27
Proportion of Acinetobacter with
Carbapenem-Resistance
Proportion of Cases
2004
28
Increase in MDR Acinetobacter VAP
Monthly Acinetobacter VAP Cases
29
Acinetobacter baumanii

• 2003 2004 4th Qtr
• Imipenem 99 29
• Amikacin 64 59
• Sulbactam 53
• Minocycline 20 50
• Cefepime 34 14
• Pip/tazo 15 6
• Ciprofloxacin 15 7
• Imipenem and meropenem are not interchangeable

30
Colistin/Polymixin E

• Cationic polypeptide
• Detergent-like disruption of outer cytoplasmic
  membrane of Gram-negative bacteria
• Used in treatment of highly resistant
  Acinetobacter and Pseudomonas when no other
  options
• Can accumulate in tissues and continue to be
  released after discontinuing therapy
• Dosing 2.5-5.0 mg/kg/d divided q12 or q8hr
• Nephrotoxicity (20-30), neurotoxicity (7)
• In vitro synergy with rifampin

31
Colistin Toxicity

• Prospective study at MGH 4/67 7/68 who received
  IM sodium colistimethate
• 288 patients received 317 courses
• Renal insufficiency 20.2
• 41 and 64 of cases in first 2 and 4 days,
  respectively
• May continue to worsen during week after
  discontinuation with improvement beginning by the
  second week
• At any dose/wt, heavy patients with increased
  risk (gt150 lbs)
• Neurotoxicity 7.3
• Respiratory insufficiency and apnea 2.1
• Contributed to patient death 4.5

Ann Intern Med 197072857-868
32
Tigecycline

• New glycylcycline derivative of minocycline
• Designed to overcome drug-resistance due to
  efflux and ribosomal protection
• In vitro activity against MRSA, VRE, and some
  Acinetobacter, but not Pseudomonas
• In complicated skin and skin-structure
  infections, the clinical cure and microbial
  eradication rates were 74 and 69
• Ongoing intra-abdominal and nosocomial pneumonia
  studies
• Compassionate use study at HMC and UWMC

33
Squeezing the Antimicrobial Balloon
Percent Change in Antimicrobial Resistance
Ceftazidime-Resistant Klebsiella
Imipenem-Resistant Pseudomonas
JAMA 19982801233-37
34
Infection Control and Resistant Pathogens

• Previous focus has been on MRSA and VRE without
  clear guidelines for gram negatives
• CDC (draft) vs. SHEA guidelines
• Role of routine active surveillance (SHEA)
• Incorporation of Multidrug-Resistant Organisms
  (CDC)
• MDR-GNBs including Acinetobacter, ESBLs
• Standard Precautions ( incorporating Body
  Substance Isolation) vs. Expanded Precautions
  (including Contact)
• Private rooms and roommate selection
• Environmental colonization and terminal cleaning
  by housekeeping

35
Isolation Precautions Debate

• Body Substance Isolation (BSI) vs. Category
  Isolation (Contact Isolation)
• Colonization vs. Infection
• BSI is a modified approach applying similar
  standards to all patients
• BSI emphasizes hand hygiene with use of
  gloves/gowns for contact with bodily substances
  (mucous membranes, wounds, fluids)

Ann Intern Med 1987107243-246
36
Role of Environmental Contamination

• 65 of nursing gowns, 58 of gloves
• 42 of gloves of nurses who had environmental
  contact, but no direct patient contact

Percent of Surfaces Positive
Infect Control Hosp Epidemiol 199718622-627
37
Reports of Controlling Acinetobacter Outbreaks

• Infect Control Hosp Epidemiol 200324284-295
• Review of 51 reports of Acinetobacter outbreaks,
  1977-2000
• Clin Infect Dis 2003361268-74
• Hand hygiene, gloves, cohorting of patients and
  nurses
• J Hosp Infect 20035397-102
• Surveillance cultures, hand hygiene,
  gloves/gowns, cohorted nursing staff
• Surg Infect 20014297-301
• Hand hygiene, isolation, dedicated
  equipment/cleaning
• Infect Control Hosp Epidemiol 200223261-7
• Required unit closure
• Infect Control Hosp Epidemiol 20012248-49
• Required unit closure

38
BSI-Plus Plan for Acinetobacter

• Hand hygiene remains the cornerstone
• BSI-Plus precautions for all Acinetobacter
  colonized or infected patients
• Surveillance cultures to identify patients
• Isolation and cohorting of colonized or infected
  patients gowns, gloves, and masks (when
  appropriate)
• Dedicated equipment and limit rounding teams
• Expansion of BSI-Plus outside of ICU for
  colonized or infected patients
• OR and radiology
• Acute care floors
• Acinetobacter rounds and compliance monitoring

39
Acinetobacter VAP
Monthly Acinetobacter VAP Cases
2004 - 2005
40
Pseudomonas susceptible to Polymyxin
Patient A Tx from NH with PNA, empyema,
bacteremia
1/28/04 3/10/04
Patient B S/P MVA, intra-abd bleed,
peri-pancreatic infection
SICU Bay previously occupied by Patient A
3/8/04 5/19/04
Roommates 4/22-4/29
Patient C Fourniers gangrene S/P radical
debridement, wound colonization and UTI
4/18/04 5/18/04
41
P. aeruginosa Susceptibilities

• 1st Qtr-03 2nd Qtr-04 1st Qtr-05
  National
• Drug H/ICU H/ICU H/ICU 2003
• Imipenem 86/84 75/61 89/88
  84
• Ciprofloxacin 59/59 50/46 71/74
  69
• Cefepime 99/100 82/78 97/100
  80
• Pip/tazo 97/100 85/76 97/98
  87
• Amikacin 99/98 94/98 96/98
• Aztreonam 70/78 48/44
  100/100

42
Fluoroquinolone Use and Resistance Among
Pseudomonas aeruginosa
Hospital use
Community use
Levofloxacin associated with resistance, but
ciprofloxacin was not
Clin Infect Dis 2004 39497-503
43
Antimicrobial Pharmacokinetic and MIC
Pharmacodynamic Relationships
Peak
Drug Concentration
Area Under the Curve (AUC)
MIC
Time
44
Pseudomonas and Fluoroquinolones

• Drug Dose Cmax MIC AUCfreeMIC
• Ciprofloxacin 400 q12 4.1 0.125
  144
• 400 q8 4.1 0.125 184
• Levofloxacin 750 q24 12.1 0.5
  152
• Gatifloxacin 400 q12 4.6 1.0
  28
• Moxifloxacin 400 q24 4.2 2.0
  10

New IDSA and ATS Guidelines recommend
Ciprofloxacin 400mg IV q8hr or Levofloxacin 750
mg qd Am J Respir Crit Care med 2005171388-416
45
Streptococcus pneumoniae Resistance

• Antimicrobial Percent Resistant
• Penicillin 13 (I) / 22 (R)
• Macrolide 31
• TMP/SMX 20-36
• Tetracyclines 8-17
• Fluoroquinolones 2

WA 2003 16 intermediate, 7 resistant
Clin Infect Dis 2002341613-20
46
Pneumococcus and Fluoroquinolones

• Drug Dose Cmax MIC90 AUCMIC90
• Gatifloxacin 400 4.2 0.5
  68
• Gemifloxacin 320 1.6 0.03
  100
• Moxifloxacin 400 4.5 0.125
  384
• Ciprofloxacin 750 3.6 2.0
  16
• Levofloxacin 500 5.7 1.0
  48
• Cutoff criterion of AUCMIC gt33.7 for
  gram-positives?

Clin Infect Dis 2003371210-5
47
High-dose, Short-course Levofloxacin for CAP

• Attempt to increase AUCMIC ratio while
  decreasing overall drug exposure
• Multi-center, randomized, double-blind study
  comparing 750 mg qd x 5 days vs. 500 mg qd x 10
  days in the treatment of CAP
• Found equivalent clinical and microbiological
  outcomes

Clin Infect Dis 200337752-60
48
Fluoroquinolone Use and Pseudomonas
Susceptibilities
49
Summary

• Resistant pathogens continue to emerge and are
  most problematic in our highly susceptible ICU
  patients
• Antimicrobial management alone will not prevent
  or contain the emergence of resistant organisms
  in the absence of strong infection control
  practices
• Importance of a team approach within the hospital
  among physicians, nurses, pharmacists, RTs, and
  health care staff